Lymphoid tumors have been pivotal in connecting cell biology to clinical observation, and this continues. The deluge of genomic and epigenomic information is increasing our understanding of pathogenesis and progression. However, in contrast to the known hallmark chromosomal changes, for example, those that upregulate B-cell lymphoma 2 (BCL2) expression, in chronic lymphocytic leukemia (CLL) and in follicular lymphoma (FL), few common single driver mutations have emerged. Although mutations in various epigenetic modifiers are frequent in several B-cell malignancies, heterogeneity both between and within cases is evident. This makes targeting with drugs difficult but allows insight into the effects of current chemotherapy/radiotherapy, which can select aggressive escape variants. Clonal heterogeneity supports the concept that cells accumulate errors and then variably exploit some changes to facilitate proliferation and/or survival. Clearly this is a 2-way process involving interaction with the complex microenvironment. A relatively underinvestigated aspect of this in lymphoma is the role of posttranslational modifications of cell-surface proteins, particularly the addition of linear and branched sugar chains, which are keys to cell-cell recognition and are often modified in tumor cells.
Mature lymphoid tumors have undergone the natural genetic rearrangements required to express the primary receptors, the surface immunoglobulins of B cells and the T-cell receptor of T cells. The IGV genes also undergo somatic hypermutation (SHM) and possibly isotype switch, which, in normal B cells, lead to antibody production. The encoding sequences are retained by tumors, providing genetic signatures for identification of the clone at different stages. The pattern also indicates the nature and maturational status of the cell of origin (COO). In some B-cell tumors, such as CLL and mantle cell lymphoma (MCL), asymmetric usage of certain IGV genes occurs, consistent with a (super)antigenic drive on the COO. Whether the COO has undergone SHM turns out to matter, especially in CLL, where IGV gene mutational levels have led to recognition of 2 subsets with distinct disease progression. Intriguingly, this may also be the case for MCL. Most lymphomas continue to express their primary receptors, but they display perturbed signaling pathways. The question is, what is driving the tumors? The answer will vary with lymphoma category, and the exciting clinical effects of inhibitors aimed at B-cell receptor signaling are revealing differences among the B-cell malignancies. Testing and refining new drugs should enable precision targeting, with potential escape variants identified by genetic monitoring then requiring a second line of attack.
The first review, by Puente et al, entitled “Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions,” compares and contrasts 2 B-cell tumors. Cross-comparisons are rarely made, and the hallmark chromosomal changes in each of these categories differ. However, within both, there are 2 subtypes, each derived from a pre–germinal center (GC) or post-GC B cell, with a poorer prognosis for the former. A similar dependence on BCR signaling and microenvironmental influences means that susceptibility to drugs and escape mechanisms show some overlap.
The second review, by Küppers and Stevenson, entitled “Critical influences on the pathogenesis of follicular lymphoma,” encompasses genetic, epigenetic, and posttranslational changes occurring during tumor development. Most cases of FL have upregulated BCL2 expression and have mutations in histone/chromatin modifiers. In addition, surface immunoglobulin, retained by all cases, virtually always carries a sequence modification in the IGV antigen-binding sites, which adds a peculiar sugar sequence. This tumor-specific posttranslational modification of the major receptor confers an ability to interact with macrophages.
The third review, by Pasqualucci and Dalla-Favera, moves on to diffuse large B-cell lymphoma (DLBCL) and is entitled “Genetics of diffuse large B-cell lymphoma.” This is a detailed analysis of the genetic and epigenetic changes documented in DLBCL. Mutational changes are extensive and complex, but shared effects on specific pathways are emerging, with potential relevance for targeted therapy. Again the COO is an influence, with at least 2 major subtypes described: GC B-cell–like, which includes cases that have transformed from FL; activated B cell–like; and an intermediate/unclassifiable subset.
The final review, by Van Arnam et al, entitled “Novel insights into the pathogenesis of T-cell lymphomas,”is focused on tumors of peripheral T lymphocytes. Compared with many B-cell tumors, recurrent and characteristic chromosomal translocations are less frequent. However, the mutational landscape is revealing the influence of perturbation of the major pathways affecting T-cell differentiation and proliferation and T-cell receptor signaling, as well as a high incidence of structural alterations in histone/chromatin modifiers. Subtypes in T-cell lymphoma are emerging, which again should allow more targeted therapies.
Altogether the 4 reviews summarize recent insights into a range of lymphoid tumors in an era of dramatically increasing knowledge of genetics, epigenetics, and tumor-environment interactions and clinical testing of precision drug targeting. Not only is this relevant to lymphomas, but as in the past, findings regarding lymphocytes will also be informative for other cancers.